Letters to the Editor  |   July 2010
How to Avoid a Heart Attack: Putting It All Together
Author Affiliations
  • Thomas A Haffey, DO
    Colorado Chapter, American College of Cardiology; Diplomate, American Board of Clinical Lipidology; Board of Directors, Southwest Lipid Association; Professor of Medicine, Western University of Health Sciences College of Osteopathic Medicine of the Pacific, Pomona, California; Kirksville College of Osteopathic Medicine-A.T. Still University, Missouri
Article Information
Cardiovascular Disorders / Preventive Medicine
Letters to the Editor   |   July 2010
How to Avoid a Heart Attack: Putting It All Together
The Journal of the American Osteopathic Association, July 2010, Vol. 110, 397-400. doi:10.7556/jaoa.2010.110.7.397
The Journal of the American Osteopathic Association, July 2010, Vol. 110, 397-400. doi:10.7556/jaoa.2010.110.7.397

“It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so.”

Mark Twain

To the Editor:  
My clinical review “How to Avoid a Heart Attack: Putting It All Together,”1 published in the May 2009 supplement to JAOA—The Journal of the American Osteopathic Association, provided osteopathic physicians and other clinicians with a framework for using a simple global program to modify the risk factors associated with myocardial infarctions. Dr Juhl and his colleagues2 take exception to my conclusion that vitamins E, C, B6, B9 (folic acid), and B12 have little usefulness as agents in the prevention of cardiovascular disease (CVD). Their letter2 resurrects a debate that has been fought in the preventive cardiology arena for the past decade. In this debate, however, a clear and decisive winner has emerged. 
There is no compelling, evidenced-based literature to support the routine use of vitamins E, C, B6, B9, or folic acid in a comprehensive program to lower patients' cardiovascular risk. There is, by contrast, a multitude of credible medical organizations—as well as a substantial body of published, credible, evidence-based studies—that discourage the use of these agents to prevent CVD. I intend this letter to serve as a brief summary of the conclusions of these organizations and studies. 
Evidence Against Vitamin E and Vitamin C Supplementation
The Mayo Clinic3 recommendations regarding vitamin E are as follows: 

Vitamin E has been proposed for the prevention or treatment of numerous health conditions, often based on its antioxidant properties. However, aside from the treatment of vitamin E deficiency (which is rare), there are no clearly proven medicinal uses of vitamin E supplementation beyond the recommended daily allowance.

Perhaps the single most compelling study to support the lack of effectiveness of vitamin E and C supplements is the MRC/BHF Heart Protection Study,4 a randomized, placebo-controlled trial in which antioxidant vitamin supplementation was examined in 20,536 individuals with coronary disease, other occlusive arterial disease, or diabetes mellitus. The study participants were randomly allocated to receive vitamin E (600 mg), vitamin C (250 mg), and beta carotene (20 mg) daily or matching placebo. Intention-to-treat comparisons of outcome were conducted among all participants. 
The MRC/BHF researchers4 found no significant differences between the vitamin and placebo groups in all-cause mortality or in deaths caused by vascular or nonvascular conditions. Nor were there any significant differences between groups in the numbers of participants having nonfatal myocardial infarction or coronary death, nonfatal or fatal stroke, or coronary or noncoronary revascularization. Thus, the investigators concluded that among the high-risk individuals in the study, the use of antioxidant vitamins did not produce any significant reductions in 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome, compared with placebo.4 
In 2003, researchers at the Cleveland Clinic5 published a meta-analysis of the state of the literature regarding the use of vitamin E and other antioxidant vitamins to prevent CVD. In the vitamin E portion of the meta-analysis, 81,788 patients were included. The overall result found by the investigators was that “vitamin E did not provide any benefit in lowering mortality compared to control treatments” and “it did not significantly decrease the risk of cardiovascular death or stroke.”5 The researchers also stated that “the lack of beneficial effect was seen consistently regardless of the doses of the vitamins used and the diversity of the patient population.” The Cleveland Clinic team concluded that the results of their study do not support the routine use of vitamin E to prevent CVD.5 
Clinical Studies
The Heart Outcomes Prevention Evaluation (HOPE) study6 followed almost 10,000 patients who were at high risk for myocardial infarctions or strokes for 4.5 years. The investigators found that participants taking natural-source vitamin E (400 IU daily) experienced “no fewer cardiovascular events or hospitalizations for heart failure or chest pain than patients taking placebo.”6 In the follow-up HOPE-2 study,7 almost 4000 of the original participants continued to take vitamin E or placebo for an additional 2.5 years. The HOPE-2 investigators concluded that after the 7 years of treatment, “[v]itamin E provided no significant protection against heart attacks, strokes, unstable angina, or deaths from cardiovascular disease or all cause mortality.”8 The researchers did report, however, that participants taking vitamin E were 13% more likely to experience, and 21% more likely to be hospitalized for, heart failure7—a unexpected finding not reported in other large studies. 
Both the HOPE6 and HOPE-27 trials provided “compelling evidence”8 that moderately high doses of vitamin E do not reduce the risk of serious cardiovascular events among men and women older than 50 years and who have established heart disease or diabetes mellitus. 
The Women's Angiographic Vitamin and Estrogen (WAVE) study9 examined the results of taking an unspecified type of vitamin E (400 IU twice daily) and vitamin C (500 mg twice daily) or placebo for more than 4 years. Not only did the vitamins provide no cardiovascular benefit, but all-cause mortality was significantly higher among the women taking the supplements (P=.045). The WAVE authors reached the following conclusion9: 

In postmenopausal women with coronary disease, neither HRT [hormone replacement therapy] nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.

The Women's Health Study10—a clinical trial of the effects of vitamin E on the heart and blood vessels of women published in 2005—included almost 40,000 healthy women aged at least 45 years who were randomly assigned to receive either natural-source vitamin E (600 IU every other day) or placebo. The women were followed for an average of 10 years. The investigators found no significant differences in rates of overall cardiovascular events (ie, combined nonfatal myocardial infarctions, strokes, and cardiovascular deaths) or all-cause mortality between the groups.10 
The Physicians' Health Study II11 is a recently published clinical trial of vitamin E and men's cardiovascular health that included almost 15,000 healthy physicians aged at least 50 years as study participants. The physicians were randomly assigned to receive synthetic alpha tocopherol (400 IU every other day), vitamin C (500 mg daily), both vitamins, or placebo. During a mean follow-up period of 8 years, intake of vitamin E, vitamin C, or both had no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, or cardiovascular mortality. Furthermore, use of vitamin E was associated with a significantly increased risk of hemorrhagic stroke (P=.04).11 
The Agency for Healthcare Research and Quality (AHRQ)12—an organization that is responsible for developing scientific information for other agencies and organizations on which to base clinical guidelines—published a systematic review of the scientific literature in 2003 that assessed evidence for the efficacy of three antioxidants in the prevention and management of CVD or in the modification of known risk factors for CVD. The antioxidants examined in the study were vitamin E, vitamin C, and coenzyme Q10. Modification of the major risk factors for CVD (ie, diabetes mellitus, hypercholesterolemia, hypertension, and smoking) has long been associated with a decreased risk of CVD. Thus, identification of interventions that could be used to successfully treat patients with CVD or to modify the underlying risk factors was of great interest to the AHRQ researchers.12 
The AHRQ researchers12 included studies in their review that focused on vitamin E, vitamin C, or coenzyme Q10—alone or in combination—for selected conditions of CVD (ie, coronary artery disease and its sequelae, stroke, heart failure, and peripheral vascular disease). Studies were also included in the analysis if they affected known risk factors for CVD, such as blood lipid levels or hypertension. 
The AHQR literature search identified 1339 articles that met the search criteria.12 Of these, the researchers identified 156 articles that represented results from 159 reports on 144 unique trials (ie, those trials reporting data not duplicated in another publication). Of the 159 reports referred for further analysis, one-third of the reports were judged to be of high quality based on the Jadad scale for assessing methodologic quality.12 
According to the AHQR team,12 the available evidence generally did not support the assertion that any benefit was associated with the use of vitamin E—either alone or in the combinations tested—for the prevention of all-cause death or cardiovascular death. Neither was there any evidence of significant harm from the same interventions. 
As reported in the Italian Group for the Study of Streptokinase in Myocardial Infarction (GISSI) trial noted in the AHQR review,12 vitamin E had an effect on overall patient mortality and cardiovascular mortality only in the “four-way” analysis (ie, comparing each arm of the 2 >2 factorial study separately)—and not in the “two-way” analysis (ie, comparing all patients who received vitamin E with all those who did not receive the vitamin). The GISSI investigators noted that the results of the four-way analysis were probably due to chance, and they concluded that vitamin E supplementation conferred no benefit to patients. 
The AHQR review12 also discussed results of the Linxian study, a large nutrition intervention trial conducted in China. The Linxian researchers reported that reduction in all-cause mortality with use of vitamin E was primarily due to a decrease in cancer-related deaths, not cardiovascular deaths. Therefore, neither the GISSI or Linxian studies supported the assertion that vitamin E supplementation results in reduction in cardiovascular mortality.12 
Regarding the risk of myocardial infarction—both fatal and nonfatal—the AHQR review12 found that results of supplementation with vitamin E are mixed. No pooled analysis has yielded significant beneficial or adverse effects for vitamin E supplementation, either alone or in combination with other supplements. 
In summary, four published studies assessing vitamin C supplementation—mostly in combination with vitamin E—provide scant evidence that these combinations of antioxidant supplements produce any benefits for patients' cardiovascular health.4,9,11,12 
Evidence Against Vitamin B Supplementation
Observational data suggest that high levels of plasma homocysteine are a risk factor for CVD, with supporting experimental data indicating that even mild to moderate elevations in homocysteine cause oxidative stress, damage the endothelium, and enhance thrombogenicity.7 Researchers have examined whether such common elevations could be corrected with vitamin supplementation. 
The idea that supplementation with folic acid and vitamins B6 and B12 would lower homocysteine levels and, in turn, lower cardiovascular events received its first blow in 2005 with the results of the Vitamin Intervention for Stroke Prevention (VISP) trial.13,14 Those results failed to show any benefit from vitamin therapy in patients with histories of stroke. 
In the HOPE-2 trial,7 some of the same investigators who reported evidence against cardiovascular benefit from vitamin E in the original HOPE trial6 reported data showing no effect from vitamin B (including folic acid) supplementation in preventing cardiovascular events. The HOPE-2 lead author, Eva M. Lonn, MD, of McMaster University in Hamilton, Ontario, Canada, said the following at a press conference at the American College of Cardiology's 55th Annual Scientific Session in 2006, where the HOPE-27 results were presented8,15: 

Because the primary study outcome is neutral, I think we have to conclude that supplementation with high-dose folic acid and vitamins B6 and B12 does not reduce major vascular events in a high-risk population with established vascular disease.

Although the results of HOPE-27 were neutral, Dr Lonn added the following about the findings of the study15: 

I think they're important, because we have been often derailed in our efforts to implement secondary prevention adequately, and the focus should be on what has been proven to work—namely, a healthy lifestyle with a good intake of fruits and vegetables, exercise, and, for those who already have had an event, certain drugs such as aspirin, statins, beta blockers, and ACE [angiotensin-converting enzyme] inhibitors, which have proven benefit.

The Norwegian Vitamin (NORVIT) trial16 found no benefit in preventing recurrent cardiovascular events from the use of folic acid and other B vitamins in patients who started taking these supplements within 7 days after myocardial infarction. The researchers, led by principal investigator Kaare Harald Bonaa, MD, of the University of Tromso in Norway, actually reported an increase in cardiovascular events with the combination of folic acid and vitamins B6 and B12. 
In an editorial17 accompanying the NORVIT trial,16 Joseph Loscalzo, MD, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, wrote that the consistency of results in three similar, though not identical, patient populations (HOPE-2,7 VISP,13,14 and NORVIT16) “leads to the unequivocal conclusion that there is no clinical benefit of the use of folic acid and vitamin B12 (with or without the addition of vitamin B6) in patients with established vascular disease.” 
Results of the NORVIT study16 also suggest that administration of combination B vitamins with the goal of reducing plasma homocysteine levels may actually increase the risk of CVD in patients, and that folic acid alone may increase patients' risk of cancer. At the Hot Line Session II of the European Society of Cardiology Congress in September 2005, Dr Bonaa noted the following18 

The results of the NORVIT trial are important because they tell doctors that prescribing high doses of B vitamins will not prevent heart disease or stroke. B vitamins should be prescribed only to patients who have B vitamin deficiency diseases.

Finally, the American Heart Association19 advises the following regarding B vitamin supplements: 

So far, no controlled treatment study has shown that folic acid supplements reduce the risk of atherosclerosis or that taking these vitamins affects the development or recurrence of cardiovascular disease.

The central question posed in the letter to the editor by Juhl et al2 is whether supplements of vitamins E and C and the B vitamins have demonstrated an evidence-based reduction in patients' cardiovascular risk. Unfortunately, the authors' criticism of the perceived deficiencies of a previously published study1 does not constitute evidence to support their position; it serves only to point out those perceived flaws. 
Multiple meta-analyses and reviews of published medical literature have convincingly established that there are few, if any, objective, evidence-based, well-designed trials to support the use of supplements of vitamins E or C or those in the B family to reduce risk of cardiovascular events. Furthermore, I am unaware of any study that advocates the use of these supplements to help patients or to rejuvenate our ailing medical delivery system. 
If Dr Juhl and his coauthors2 seek to establish the medical value of these supplements, I would recommend that they design, participate in, and publish a study to establish their yet unproven hypothesis. Until such a goal is accomplished, my opinion (shared by researchers at the Mayo Clinic,3 the Cleveland Clinic,5 the AHRQ,12 and the American Heart Association19) is that published evidence clearly does not support the use of vitamins E, C, B6, B9, or B12 to improve patients' cardiovascular health. 
Haffey TA. How to avoid a heart attack: putting it all together. J Am Osteopath Assoc. 2009;109(suppl 1):S14-S20. Accessed June 22, 2010.
Juhl JH, Ostrow GL, Gleyzer M, Firshein R, Kulick A, Gordon-Cohen B, et al. How to avoid a heart attack: putting it all together [letter]. J Am Osteopath Assoc. 2010;110(5):268-270. Accessed June 22, 2010.
Vitamin E. Mayo Clinic Web site. Accessed June 22, 2010.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):23-33.
Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet. 2003;361(9374):2017-2023.
Yusuf S, Dagenais G, Pogue J, Bosch, J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):154-160. Accessed June 22, 2010.
Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, et al; HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293(11):1338-1347.
Lonn EM, Yusuf S; The HOPE-2 Investigators. Homocysteine lowering in stable chronic vascular disease: The Heart Outcomes Prevention Evaluation (HOPE-2 trial). In: Program and abstracts from the 55th Annual Scientific Session of the American College of Cardiology, Late-Breaking Clinical Trials II; March 11-14, 2006; Atlanta, GA. Abstract 411-6.
Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288(19):2432-2440.
Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294(1):56-65.
Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial [published online ahead of print November 9, 2008]. JAMA. 2008;300(18):2123-2133.
Shekelle P, Morton S, Hardy M. Effect of Supplemental Antioxidants Vitamin C, Vitamin E, and Coenzyme Q10 for the Prevention and Treatment of Cardiovascular Disease. Summary, Evidence Report/Technology Assessment: Number 83. Rockville, MD: Agency for Healthcare Research and Quality; June 2003. AHRQ publication 03-E042. Accessed June 22, 2010.
Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention for Stroke Prevention trial: an efficacy analysis [published online ahead of print October 20, 2005]. Stroke. 2005;36(11):2404-2409. Accessed June 22, 2010.
Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291(5):565-575.
Jeffrey S. HOPE-2, NORVIT: No CV benefit from reducing homocysteine with folic acid and B vitamins. Medscape Medical News. March 12, 2006. Accessed June 22, 2010.
Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction [published online ahead of print March 12, 2006]. N Engl J Med. 2006;354(15):1578-1588. Accessed June 22, 2010.
Loscalzo J. Homocysteine trials—clear outcomes for complex reasons [editorial]. N Engl J Med. 2006;354(15):1629-1632.
Dellios G. High doses of B vitamins after heart attack, stroke does not lower risk of recurrence. Medical News Today. September 7, 2005. Accessed July 12, 2010.
Homocysteine, folic acid and cardiovascular disease. American Heart Association Web site. Accessed June 22, 2010.